The Neuropsychology Core Laboratory has several findings this year. We assessed the roles of COMT val158met and BDNF val66met functional polymorphisms as they pertain to working/episodic memory. [unreadable] [unreadable] 1. Working memory is critically mediated by dopamine tuning of signal-to-noise in cortical neural assemblies. Little is known about the distributed neuronal networks impacted by dopamine modulation in the component process of working memory. Here, we used the COMT val158met genotype as an index of relative cortical dopamine bioavailability and tuning efficiency, to examine the spatial and subprocess specificity by which dopamine modulation occurs within the prefrontal-parietal-striatal network during working memory processes. We found manipulating and rapidly updating representations were sensitive to dopamine modulation of neural signaling in a larger prefrontal-parietal-striatal network. These findings add to the integration of dopamine signaling in basic cortical assemblies with their roles in specific human brain networks during the orchestration of information processing in working memory.[unreadable] [unreadable] 2. Another study examined whether 3 mutations in COMT affected dopamine regulated prefrontal cortical activity during working memory tasks. A large sample, SCZ (325), their non-psychotic siblings (359), and HC (330) completed tests of working memory function. Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Only 1 COMT mutation (val158met) showed significant or near-significant effects on all conditions of the n-back. None of the other mutations showed main effects by themselves. We extended earlier findings of a val158 met effect on working memory function, and suggest that contributions of alleles within COMT may modulate the val158met effect in a nonlinear manner.[unreadable] [unreadable] 3. A third study studied the impact of BDNF val66met in a verbal recognition paradigm evaluating depth of encoding and delays of recall and analyses of hits for previously presented words. BDNF val/val (24) and met carriers (24), all healthy controls, showed significant effects on hits and discriminability. BDNF did not impact the level of encoding or delay.[unreadable] [unreadable] In our continuing efforts to further characterize cognitive deficits as an intermediate phenotype in schizophrenia, we performed studies using patients with schizophrenia (SCZ), their non-psychotic siblings and healthy control (HC) subjects.[unreadable] [unreadable] 1. In one study we examined a large cohort of 302 SCZ, 240 sibs and 346 HC to determine the frequency with which frontal release signs occur in these three groups, and specifically to assess the familiarity of these signs by comparing the SCZ and sib cohorts. Frontal release signs (also known as primitive reflexes) are a subset of neurological soft signs: they consist of a group if involuntary motor responses which are normally found early in postnatal development and are subsequently inhibited, but may be 'released' from inhibition by cerebral, usually frontal damage. Second, we sought to investigate the association between frontal release signs and cognitive impairment, with a focus on frontal lobe function as well as more general cognitive measures, such as full-scale IQ. Our results show the total score of frontal release signs were greater in SCZ (1.5) than siblings (0.54) or HC (0.42). In the SCZ group, frontal release signs scores showed an inverse correlation with IQ. Our findings of relationships between frontal release signs and cognitive assays of cortical dysfunction and the increased frequency of these signs in people with SCZ implicate a cortical origin for these clinical signs and evidence of frontal lobe dysfunction in this disorder.[unreadable] [unreadable] 2. Another study examined the intradimensional/extradimensional (ID/ED) set-shifting performance in 147SCZ, 131 sibs, and 303 HC subjects. In set-shifting, subjects need to shift between performing two tasks when presented a cue. We found that nearly all HC and sibs completed the task successfully, which is in stark contrast to with the SCZ group. Performance across the sibs and HC was quite similar, but these two groups differed significantly in terms of the number of stages until failure. Where SCZ demonstrated severe ID/ED deficits, their sibs were minimally impaired and did not run in families. The results suggest that impairments on set-shifting assessed by ID/ED are strongly associated with clinical illness, but these impairments are not a promising intermediate phenotype.[unreadable] [unreadable] 3. Our group sought to characterize verbal and visual memory deficits as another intermediate phenotype for SCZ. It is unclear whether deficits lie in encoding or savings and whether the deficits are heritable. We tested episodic memory using Logical Memory and Visual Reproduction tasks on 162 SCZ, 146 sibs, and 205 HC. We assessed intermediate encoding and 30min and 24hr delayed recall as well as saving scores at 30min and 24hr. SCZ showed deficits for both verbal and visual recall and sibs were impaired for verbal recall. There were marked verbal recall deficits in both SCZ and sibs making it a potential non-diagnostic indicator of genetic liability for illness. Visual recall impairment appears to mark a SCZ clinical phenotype.[unreadable] [unreadable] 4. Lastly, we examined impairments in source monitoring, which has been widely reported in SCZ. Source monitoring requires one to retrieve the content of an event, but also the temporal and spatial context in which the event took place. In our study, 21 SCZ and 21 HC completed a task where memory for affective and neutral word pairs was assessed in conjunction with memory for both source and temporal information. Our goal was to evaluate whether SCZ is linked to a deficit in binding different elements in memory together, assess whether SCZ would exhibit differential memory performance for emotional versus neutral material, and to assess whether clinical symptoms would affect source monitoring performance. The findings show that SCZ performed more poorly than controls overall, and tended to exhibit a fractionated retrieval of word pairs. Intellectual level and overall verbal memory performance were significantly correlated with context binding performance for positive and neutral word pairs. We also show that clinical symptoms were unrelated to source monitoring performance.